Association between Helicobacter pylori seropositivity and the hemoglobin A1c/high-density lipoprotein cholesterol ratio in U.S. adults: evidence from NHANES

Abstract

Background:

Helicobacter pylori (H. pylori) infection is associated with insulin resistance and metabolic syndrome. This study investigates the association between H. pylori seropositivity and the newly proposed hemoglobin A1c/high-density lipoprotein cholesterol ratio (HbA1c/HDL-C ratio) in a nationally representative U.S. population.

Methods:

Data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES) were analyzed. Multivariable linear regression models assessed the association between H. pylori seropositivity and the HbA1c/HDL-C ratio. Subgroup analyses were performed to evaluate the consistency of the association across different demographic and clinical strata. Generalized additive models with smoothing splines and threshold effect analysis was conducted to identify potential nonlinear relationships.

Results:

The cross-sectional analysis comprised 2,909 participants, including 1,254 with H. pylori seropositivity. After multivariable adjustment, a significant positive association was found between H. pylori seropositivity and the HbA1c/HDL-C ratio (β: 0.28, 95% CI: 0.13, 0.42). Subgroup analyses revealed a stronger association among non-diabetic individuals compared to diabetic individuals. A “L”-shaped relationship was observed, with an inflection point at an HbA1c/HDL-C ratio of 4.81. Below this threshold, H. pylori seropositivity was positively associated with the HbA1c/HDL-C ratio. Above this threshold, the association was no longer statistically significant.

Conclusion:

This study identifies a significant association between H. pylori seropositivity and the HbA1c/HDL-C ratio, suggesting that metabolic dysfunction may be linked to H. pylori infection. Future longitudinal studies are needed to establish causality and explore underlying mechanisms.

1 Introduction

Helicobacter pylori (H. pylori) infection is one of the most prevalent chronic bacterial infections in the world, affecting about half of the global population (1, 2). It is a major cause of several gastrointestinal disorders, including chronic gastritis, peptic ulcer and gastric cancer (3, 4). In addition, many extra-gastric diseases have been shown to be associated with H. pylori infection, such as metabolic, cardiovascular and neurological disorders (5–7).

Emerging evidence suggests that H. pylori infection may contribute to systemic metabolic disturbances, including insulin resistance (IR) and metabolic syndrome (8–10). This association appears to be bidirectional, with individuals who already exhibit metabolic disturbances being more prone to persistent H. pylori infection (11). However, the existing literature presents inconsistent results, underscoring the necessity for novel biomarkers to disentangle this intricate interplay. In recent years, the HbA1c/HDL-C ratio has been introduced as a comprehensive indicator of both glucose and lipid metabolism. Hemoglobin A1c (HbA1c), a marker reflecting average blood glucose levels over the past 2–3 months, provides insight into long-term glycemic control (12, 13). On the other hand, high-density lipoprotein cholesterol (HDL-C), known for its anti-inflammatory and antioxidant properties, plays a key role in lipid metabolism and is generally regarded as a protective factor against cardiovascular diseases (14). Thus, the HbA1c/HDL-C ratio serves as a refined measure of the interplay between glucose regulation and lipid balance, offering valuable information about overall metabolic state. This ratio has gained considerable attention for its potential in assessing the risk of various conditions, including carotid atherosclerosis (15), stroke (16), and metabolic associated fatty liver disease (17). Despite its promising clinical significance, no studies have yet examined the relationship between the HbA1c/HDL-C ratio and H. pylori infection.

This study aims to investigate the association between H. pylori seropositivity and the HbA1c/HDL-C ratio in a nationally representative sample of U.S. adults. By exploring this relationship, we seek to identify potential metabolic markers for H. pylori susceptibility and provide new insights into the interplay between metabolic health and infectious diseases.

2 Methods

2.1 Study design and population

The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional program designed to assess the health and nutritional status of the non-institutionalized civilian population in the U.S. (18, 19). Employing a complex, multi-stage probability sampling design, NHANES collects data through structured interviews, standardized physical examinations, and comprehensive laboratory analyses, providing a robust platform for evaluating a wide range of health indicators (19–21). All study protocols were reviewed and approved by the Ethics Review Board of the National Center for Health Statistics, and written informed consent was obtained from all participants.

This study utilized data from the 1999–2000 NHANES cycle. Initially, 4,480 participants aged 20 years or older were included. After excluding individuals with incomplete data on the HbA1c/HDL-C ratio (n = 764) and H. pylori serological status (n = 116), as well as those with missing covariates such as education level (n = 13), marital status (n = 431), poverty income ratio (PIR) (n = 484), drinking status (n = 143), smoking status (n = 3), and body mass index (BMI) (n = 17), a total of 2,909 participants were included in the final analysis (Figure 1).

Figure 1

2.2 Assessment of Helicobacter pylori seropositivity status

Helicobacter pylori seropositivity status was assessed using enzyme-linked immunosorbent assay (ELISA) to quantify anti-H. pylori immunoglobulin G (IgG) antibody levels (22). Participants were classified into two groups based on established ELISA cutoff values: H. pylori-positive (optical density [OD] value ≥1.1) and H. pylori-negative (OD value < 0.9). Ambiguous results within the range of 0.9 to 1.1 were excluded from the analysis to ensure precise statistical outcomes, consistent with previous epidemiological studies (23–25).

2.3 Assessment of the HbA1c/HDL-C ratio

Fasting blood samples were analyzed to measure HbA1c and HDL-C levels. The HbA1c/HDL-C ratio was calculated by dividing HbA1c (%) by HDL-C (mg/dL) (15). Participants were categorized into quartiles (Q1 to Q4) based on their HbA1c/HDL-C ratio values, with quartile thresholds determined by dividing the study population into four equal groups.

2.4 Assessment of covariates

To ensure comprehensive adjustments in the analysis, relevant sociodemographic characteristics, lifestyle behaviors, and comorbid health conditions were included as covariates. Sociodemographic variables encompassed age, sex, race, education level, marital status, and PIR. Lifestyle factors included drinking status (classified as <12 or ≥12 alcoholic drinks per year) and smoking status (categorized as never, former, or current smoker). Health conditions were assessed using a combination of self-reported data and objective clinical measurements. BMI was calculated as weight in kilograms divided by height in meters squared (kg/m²) and classified into normal weight (<25), overweight (≥25 and <30), and obesity (≥30) (26). Hypertension was defined as a self-reported physician diagnosis, use of antihypertensive medications, or elevated blood pressure (systolic ≥130 mmHg or diastolic ≥80 mmHg) (27). Cardiovascular disease, encompassing coronary heart disease, angina, congestive heart failure, myocardial infarction, and stroke, was ascertained through self-reported diagnoses provided by healthcare professionals (28).

2.5 Statistical analysis

All statistical analyses were conducted using appropriate NHANES sampling weights to account for the complex, multi-stage cluster survey design. Baseline characteristics of participants were described using weighted means (95% confidence intervals [CIs]) for continuous variables and weighted percentages (95% CIs) for categorical variables. Differences in baseline characteristics were assessed using weighted linear regression for continuous variables and weighted chi-square test for categorical variables.

The association between H. pylori seropositivity and the HbA1c/HDL-C ratio was evaluated using multivariable linear regression models. Crude model was unadjusted, Model 1 adjusted for age, sex, and race, and Model 2 further adjusted for education, marital status, PIR, drinking status, smoking status, BMI, hypertension, diabetes, and cardiovascular disease. Results were reported as beta (β) coefficients with corresponding 95% CIs. Subgroup analyses were conducted to examine the association between H. pylori seropositivity and the HbA1c/HDL-C ratio across different age, sex, race, PIR, BMI, and disease histories (hypertension and cardiovascular disease). Interaction tests were used to evaluate the consistency of these associations across subgroups.

As a sensitivity analysis, we performed logistic regression analyses with H. pylori seropositivity as the dependent variable and the HbA1c/HDL-C ratio as the independent variable. Both continuous and quartile-based forms of the HbA1c/HDL-C ratio were included in the regression analyses. Results were reported as odds ratios (ORs) with corresponding 95% CIs.

To explore potential non-linear relationships between H. pylori seropositivity and the HbA1c/HDL-C ratio, generalized additive models with smoothing splines were employed. Additionally, recursive algorithms and two-stage logistic models were utilized to detect any potential inflection points in the relationship. Likelihood ratio tests were performed to compare the fit of single logistic regression models with that of two-stage logistic models.

All analyses were performed using R (http://www.R-project.org, version 4.3.1) and EmpowerStats (http://www.empowerstats.com, version 4.2). Statistical significance was defined as a two-sided p value < 0.05.

3 Results

3.1 Baseline characteristics

This analysis included 2,909 U.S. adults with a weighted mean age of 44.65 years (95% CI: 43.59, 45.70), of whom 48.22% were male and 43.8% exhibited H. pylori seropositive. Table 1 summarizes the comparative analysis of demographic, socioeconomic, and clinical characteristics between H. pylori seropositive and seronegative participants. Within the H. pylori seropositive group, there was a greater proportion of older individuals and Mexican Americans. They also had lower levels of education, lower PIR, and were more likely to be married or living with a partner. Additionally, H. pylori seropositive participants were more likely to be smokers and less likely to consume alcohol. Furthermore, individuals with H. pylori seropositive exhibited higher prevalence rates of hypertension, diabetes, and cardiovascular disease. However, traditional metabolic markers, such as TC, TG, LDL-C, and uric acid, did not differ significantly between the two groups. Notably, the HbA1c/HDL-C ratio was significantly higher among H. pylori seropositive participants.

3.2 Association between Helicobacter pylori seropositivity and the HbA1c/HDL-C ratio

Table 2 presents the associations between H. pylori seropositivity and HbA1c/HDL-C ratio. The results indicated that H. pylori seropositivity was positively associated with the HbA1c/HDL-C ratio in the unadjusted model (β: 0.55, 95% CI: 0.41, 0.69), the partially adjusted model (β: 0.36, 95% CI: 0.22, 0.51), and the fully adjusted model (β: 0.28, 95% CI: 0.13, 0.42).

3.3 Subgroup analysis

Subgroup analyses and interaction tests were conducted to evaluate the consistency of the association between H. pylori seropositivity and the HbA1c/HDL-C ratio across various demographic and clinical subgroups, including age, sex, race, PIR, BMI, hypertension, diabetes, and cardiovascular disease (Figure 2). The positive association between H. pylori seropositivity and the HbA1c/HDL-C ratio was generally consistent across most subgroups (P for interaction >0.05). However, a significant interaction was identified for diabetes status (P for interaction = 0.038). Specifically, the association was stronger in individuals without diabetes (β: 0.31, 95% CI: 0.19, 0.43) compared to those with diabetes (β: 0.21, 95% CI: −0.03, 0.45).

Figure 2

3.4 Sensitivity analysis

To further validate the robustness of our findings, we conducted additional sensitivity analyses. In the fully adjusted model, participants in the highest quartile (Q4) of the HbA1c/HDL-C ratio exhibited an 84% increased probability of H. pylori seropositivity (OR: 1.75, 95% CI: 1.38, 2.44) compared to those in the lowest quartile (Q1). Notably, trend tests confirmed the statistical significance of the overall positive association between the HbA1c/HDL-C ratio and H. pylori seropositivity (all P for trend <0.05) (Supplementary Table 1).

3.5 Dose–response relationship between Helicobacter pylori seropositivity and the HbA1c/HDL-C ratio

Generalized additive models with smoothing splines revealed a nonlinear, L-shaped association between the HbA1c/HDL-C ratio and H. pylori seropositivity (Figure 3). Threshold effect analysis identified an inflection point at an HbA1c/HDL-C ratio of 4.81. Below this threshold, a significant positive association was observed between the HbA1c/HDL-C ratio and H. pylori seropositivity (OR: 1.29, 95% CI: 1.14, 1.46), whereas no significant association was observed above the threshold (OR: 1.02, 95% CI: 0.96, 1.09). The log-likelihood ratio test confirmed the superiority of the two-piecewise linear regression model over the one-line linear model (p = 0.003) (Supplementary Table 2). We constructed stratified curves for the association between the HbA1c/HDL-C ratio and H. pylori seropositivity by diabetes status (Supplementary Figure 1). In non-diabetic individuals, the HbA1c/HDL-C ratio exhibited a linear association with H. pylori seropositivity (OR: 1.19, 95% CI: 1.10, 1.28), and the log-likelihood ratio test (p = 0.205) supported the adequacy of the linear model. Among diabetic individuals, no significant association between the HbA1c/HDL-C ratio and H. pylori seropositivity was found (Supplementary Table 3).

Figure 3

4 Discussion

In this cross-sectional study conducted among U.S. population, we identified a significant positive association between H. pylori seropositivity and the HbA1c/HDL-C ratio. Notably, we observed a “L”-shaped relationship between H. pylori seropositivity and the HbA1c/HDL-C ratio, with an inflection point at 4.81. Below this threshold, H. pylori seropositivity was positively associated with the HbA1c/HDL-C ratio. However, above this value, no significant association was detected.

H. pylori infection may increase the risk of metabolic dysfunction. A systematic review has reported a positive correlation between H. pylori infection and metabolic syndrome, with infected individuals exhibiting elevated levels of TG, fasting blood glucose (FBG), BMI, and reduced HDL-C (29). Several studies have also demonstrated that H. pylori infection is linked to abnormal glucose metabolism and an increased risk of diabetes (30–32). Specifically, individuals with H. pylori infection exhibit significantly higher HbA1c levels compared to uninfected individuals, and a positive correlation has been observed between H. pylori infection and elevated HbA1c levels in diabetic patients (33). These findings suggest that H. pylori infection may be closely associated with IR-related disorders. However, the relationship between H. pylori infection and markers such as HbA1c and IR remains controversial. For instance, a large cross-sectional study involving 37,263 participants found that H. pylori infection was associated only with dyslipidemia, showing no significant correlation with FBG or HbA1c levels (34). In addition to its potential impact on glucose metabolism, H. pylori infection has been shown to significantly influence lipid profiles. Studies indicate that individuals with H. pylori infection tend to exhibit elevated levels of TC, TG and LDL-C, alongside reduced HDL-C levels (35–37). Notably, the prevalence of dyslipidemia is significantly lower in individuals who have undergone H. pylori eradication compared to those with active infection (38). Eradication of H. pylori has been associated with improved lipid profiles, including increased HDL-C levels and decreased TG and LDL-C levels (39, 40). These findings demonstrate the complexity of the relationship between H. pylori infection and metabolic disorders and suggest that more research is needed to focus on the association between H. pylori infection and abnormal glucose and lipid metabolism.

Glucose and lipid metabolism interact through complex physiological and pathological processes (41, 42). The triglyceride-glucose (TyG) index, derived from FPG and TG levels, has emerged as a reliable marker of IR and metabolic dysfunction (43, 44). Previous studies have shown that an elevated TyG index is associated with an increased risk of H. pylori infection (24, 45). Compared to the short-term glucose indicators used in the TyG index, HbA1c reflects long-term glucose control and provides a more stable measure than fasting glucose (46). Our findings are consistent with studies using the TyG index, revealing the close association between H. pylori seropositivity and glycolipid metabolism. The HbA1c/HDL-C ratio may offer more stable and clinically meaningful insights into the relationship between H. pylori infection and metabolic dysfunction.

In this study, we identified a saturation effect in the relationship between H. pylori seropositivity and the HbA1c/HDL-C ratio using segmented regression analysis. Within the lower range of the HbA1c/HDL-C ratio, mild disturbances in glucose and lipid metabolism were associated with a higher probability of H. pylori seropositivity. However, beyond a certain threshold, this association was no longer significant. This saturation effect aligns with previous observations of nonlinear relationships between metabolic indicators and health outcomes (16, 47), suggesting that the association between metabolic status and H. pylori infection may vary depending on the severity of metabolic disturbances.

Subgroup analyses revealed that the association between H. pylori seropositivity and the HbA1c/HDL-C ratio was more pronounced in individuals without diabetes than in those with diabetes. This discrepancy may be attributed to the complex metabolic disturbances in individuals with diabetes, characterized by hyperglycemia and dyslipidemia, which could obscure the relationship between H. pylori seropositivity and the HbA1c/HDL-C ratio (48, 49). Unfortunately, our study lacked detailed data on disease duration, treatment regimens, and the presence of complications, limiting our ability to explore these potential influences. Additionally, glycemic and lipid-lowering therapies, which are common in diabetes management, may alter the measurement of the HbA1c/HDL-C ratio and impact H. pylori colonization or eradication, thereby attenuating the observed association (50, 51). Our findings suggest that H. pylori seropositivity is positively associated with the HbA1c/HDL-C ratio, especially in non-diabetic populations. Future research should explore the mechanisms underlying this association and develop personalized strategies for metabolic management.

The potential mechanisms underlying the association between the HbA1c/HDL-C ratio and H. pylori infection are multifaceted. H. pylori infection induces systemic inflammation through the release of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6, which disrupt insulin signaling pathways and exacerbate insulin resistance (52, 53). Moreover, H. pylori infection may alter the gastric environment, influencing gut microbiota composition and contributing to systemic inflammation and metabolic dysregulation (54, 55). The relationship between metabolic disorders and H. pylori infection appears to be bidirectional. Metabolic dysfunction, characterized by IR, hyperglycemia, and dyslipidemia, promotes oxidative stress and impairs gastric mucosal defenses, thereby creating a favorable environment for H. pylori colonization and persistence (10, 56, 57). Additionally, IR-related autonomic dysfunction may slow gastrointestinal motility and reduce gastric acid secretion, further facilitating H. pylori survival (58–60). These interconnected mechanisms highlight the complex interplay between metabolic health and H. pylori infection, with the exact mechanisms warranting further investigation.

This study is the first to investigate the association between H. pylori seropositivity and the HbA1c/HDL-C ratio. A key strength of this study is its use of a large, nationally representative sample of U.S. adults, which enhances the generalizability of the findings to broader populations. However, several limitations should be noted. First, as a cross-sectional study, it cannot establish a causal relationship between H. pylori seropositivity and the HbA1c/HDL-C ratio. Further longitudinal studies are needed to clarify the directionality of this association. Second, the NHANES database provides only serological data on H. pylori infection status, which precludes differentiation between past and current infections among seropositive participants. Although serology is a widely used and reliable method for assessing H. pylori status in large epidemiological studies (25, 28), it does not capture the activity of infection, thereby limiting our ability to assess the relationship between chronic versus acute infection and metabolic disturbances. Third, there may be unmeasured confounding factors, such as genetic predisposition, unaccounted medication use, and environmental influences, which could affect the observed association between H. pylori seropositivity and the HbA1c/HDL-C ratio. Finally, the study focused exclusively on a U.S. population, which may limit the generalizability of the findings to other ethnic or geographic groups.

5 Conclusion

This study identifies a positive association between H. pylori seropositivity and the HbA1c/HDL-C ratio in a nationally representative sample. The findings suggest that this metabolic marker may serve as a potential indicator of H. pylori infection in clinical settings. Future longitudinal studies are needed to establish causality and explore underlying mechanisms.

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